Packaged antimicrobial medical device having improved shelf life and method of preparing same

ABSTRACT

A packaged antimicrobial suture. The packaged antimicrobial suture includes an inner package having a source of antimicrobial agent, the source of antimicrobial agent comprising a plurality of patches, each patch having a pair of antimicrobial material reservoirs; at least one suture positioned within the inner package, the at least one suture comprising one or more surfaces; and an outer package having an inner surface, the outer package having the inner package positioned within; wherein the at least one suture, the inner package and the inner surface of the outer package are subjected to time, temperature and pressure conditions sufficient to transfer an effective amount of the antimicrobial agent from the antimicrobial agent source to the at least one suture and the inner package, thereby substantially inhibiting bacterial colonization on the at least one suture and the inner package. A method of making a packaged antimicrobial suture having is also provided.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.13/727,340, filed Dec. 26, 2012, which claims the benefit of U.S.Provisional Application No. 61/621,337 filed Apr. 6, 2012, the contentsof which are hereby incorporated by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to an antimicrobial medical device and anantimicrobial packaged medical device and their methods of making.

BACKGROUND OF THE INVENTION

Each year, patients undergo a vast number of surgical procedures in theUnited States. Current data shows about twenty-seven million proceduresare performed per year. Post-operative or surgical site infections(“SSIs”) occur in approximately two to three percent of all cases. Thisamounts to more than 675,000 SSIs each year.

The occurrence of SSIs is often associated with bacteria that cancolonize on implantable medical devices used in surgery. During asurgical procedure, bacteria from the surrounding atmosphere may enterthe surgical site and attach to the medical device. Specifically,bacteria can spread by using the implanted medical device as a pathwayto surrounding tissue. Such bacterial colonization on the medical devicemay lead to infection and trauma to the patient. Accordingly, SSIs maysignificantly increase the cost of treatment to patients.

Implantable medical devices that contain antimicrobial agents applied toor incorporated within have been disclosed and/or exemplified in theart. Examples of such devices are disclosed in European PatentApplication No. EP 0 761 243. Actual devices exemplified in theapplication include French Percuflex catheters. The catheters weredip-coated in a coating bath containing2,4,4′-tricloro-2-hydroxydiphenyl ether (Ciba Geigy Irgasan (DP300)) andother additives. The catheters then were sterilized with ethylene oxideand stored for thirty days. Catheters coated with such solutionsexhibited antimicrobial properties, i.e., they produced a zone ofinhibition when placed in a growth medium and challenged withmicroorganism, for thirty days after being coated. It is not apparentfrom the application at what temperature the sterilized, coatedcatheters were stored.

Most implantable medical devices are manufactured, sterilized andcontained in packages until opened for use in a surgical procedure.During surgery, the opened package containing the medical device,packaging components contained therein, and the medical device, areexposed to the operating room atmosphere, where bacteria from the airmay be introduced. Incorporating antimicrobial properties into thepackage and/or the packaging components contained therein substantiallyprevents bacterial colonization on the package and components once thepackage has been opened. The antimicrobial package and/or packagingcomponents in combination with the incorporation of antimicrobialproperties onto the medical device itself would substantially ensure anantimicrobial environment about the sterilized medical device.

SUMMARY OF THE INVENTION

In one aspect, disclosed herein is a packaged antimicrobial suture. Thepackaged antimicrobial suture includes an inner package having a sourceof antimicrobial agent, the source of antimicrobial agent comprising aplurality of patches, each patch having a pair of antimicrobial materialreservoirs; at least one suture positioned within the inner package, theat least one suture comprising one or more surfaces; and an outerpackage having an inner surface, the outer package having the innerpackage positioned within; wherein the at least one suture, the innerpackage and the inner surface of the outer package are subjected totime, temperature and pressure conditions sufficient to transfer aneffective amount of the antimicrobial agent from the antimicrobial agentsource to the at least one suture and the inner package, therebysubstantially inhibiting bacterial colonization on the at least onesuture and the inner package.

In one embodiment, the antimicrobial agent is selected from the groupconsisting of halogenated hydroxyl ethers, acyloxydiphenyl ethers, andcombinations thereof.

In another embodiment, the effective amount of the antimicrobial agenttransferred from the source of antimicrobial agent to the suture and theinner package is transferred during an ethylene oxide sterilizationprocess.

In yet another embodiment, the step of subjecting the suture, the innerpackage and the inner surface of the outer package to conditionssufficient to transfer an effective amount of the antimicrobial agentcomprises the steps of placing the outer package having the innerpackage and the suture therein in a sterilization unit, heating thesterilization unit to a first temperature, adjusting the pressure in thesterilization unit to a first pressure value, injecting steam into thesterilization unit to expose the inner surface of the outer package, theinner package and the suture to water for a first period of time,adjusting the pressure within the sterilization unit to a secondpressure value, introducing a chemical sterilization agent into thesterilization unit, maintaining the chemical sterilization agent in thesterilization unit for a second period of time to render a sufficientamount of microorganisms non-viable, removing residual moisture andchemical sterilization agent from the suture, and drying the packagedantimicrobial suture to a desired moisture level.

In still another embodiment, the inner package comprises a containmentcompartment having an outer cover.

The present invention also relates to a method of making a packagedantimicrobial suture. The method includes the steps of providing aninner package having a source of antimicrobial agent, the source ofantimicrobial agent comprising a plurality of patches, each patch havinga pair of antimicrobial material reservoirs; positioning at least onesuture within the inner package, the at least one suture comprising oneor more surfaces; covering the inner package with an outer packagehaving an inner surface; and subjecting the at least one suture, theinner package and the inner surface of the outer package to time,temperature and pressure conditions sufficient to transfer an effectiveamount of the antimicrobial agent from the antimicrobial agent source tothe at least one suture and the inner package, thereby substantiallyinhibiting bacterial colonization on the at least one suture and theinner package.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention is further explained in the description that follows withreference to the drawings illustrating, by way of non-limiting examples,various embodiments of the invention wherein:

FIG. 1 is a top plan view of one form of a packaged antimicrobialmedical device, in accordance herewith, wherein the outer package hasbeen fully removed to reveal a containment compartment.

FIG. 2 is a top plan view of the containment compartment of FIG. 1 ,wherein the outer cover of the containment compartment has been removedto fully expose the base member.

FIG. 3 is a plan view of the underside of the outer cover of thecontainment compartment, showing a plurality of antimicrobial agentreservoirs disposed about the periphery of the cover.

FIG. 4 is a bottom plan view of the containment compartment of thepackaged antimicrobial medical device of FIG. 1 .

FIG. 5 is a top plan view of the packaged antimicrobial medical deviceof FIG. 1 , wherein the outer package has been partially removed toreveal a portion of the containment compartment.

DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION

Reference is now made to FIGS. 1-5 wherein like numerals are used todesignate like elements throughout.

Packaged Antimicrobial Medical Device

Referring now to FIGS. 1-5 , one embodiment of a packaged antimicrobialmedical device 10 is shown. Packaged antimicrobial medical device 10includes an inner package 11 having a source of antimicrobial agent. Amedical device 14, which may be a needle 16 and suture 18 having one ormore surfaces 20 is positioned within the inner package 11. In oneembodiment, inner package 11 comprises a containment compartment 12 andan outer cover 22.

As shown, inner surface 24 may be provided with a plurality of patches54. In one form, each patch has a pair of antimicrobial materialreservoirs 56, formed from a material capable of serving as a reservoir.In one form, antimicrobial agent reservoirs 56 may be formed a porousmaterial, such as medical grade paper, or a permeable polymeric film orfabric having a matrix structure. Suitable polymeric materials mayinclude a polyolefin or polyolefin blend, such as polyethylene,polypropylene or blends thereof. In one form, the permeable materialcomprises TYVEK® nonwoven material, manufactured by E. I. du Pont deNemours and Company of Wilmington, Del., and made from high-densitypolyethylene fibers. Advantageously, the antibacterial material cantransfer from the patches 54 to the medical device(s) 14 and interiorsurfaces of the package. In one form, the plurality of patches 54 arepositioned about an outer periphery of the inner surface 24 of outercover 22.

Optionally, the outer cover 22 may have one surface that may be coatedwith an adsorbent material. In one embodiment, the adsorbent material iseffective to adsorb a portion of the antimicrobial agent over time. Anouter package 50 having an inner surface 52 is provided to seal theinner package 11 when positioned within.

The containment compartment 12 of packaged antimicrobial medical device10 includes a base member 26 and a channel cover member 28. Base member26 includes a top side, bottom side, and an outer periphery 30. Asshown, an outer cover 22 may be positioned upon channel cover member 28and within outer periphery 30, to at least partially enclose medicaldevice 14. The base member 26 may be a substantially flat substantiallysquare member having rounded corners. While in the case of packagedsutures, it may be desired that the base member 26 of packagedantimicrobial medical device 10 be substantially square with roundedcorners, other configurations can be used including circular, oval,polygonal, rectangular with rounded corners, and the like andcombinations thereof and equivalents thereof. Channel cover 28 includesa top side, bottom side, and periphery 32.

The packaged antimicrobial medical device 10 of the present inventionmay be assembled in the following manner. Base member 26 is aligned withchannel cover member 28 so that rivets 34, if employed are in alignmentwith the rivet receiving holes 36, and locating pins, if employed, arein alignment with corresponding openings. Also, winding pins 38, ifemployed, are aligned with corresponding openings 40. Then, channelcover member 28 is then mounted to base member 26 such that rivets, ifemployed, are inserted into and through corresponding holes and locatingpins, if employed, are inserted through corresponding holes. The ends ofthe rivets 34, if employed, may be spread by using conventionaltechniques such as heating, ultrasonic treatments, and the like, so thatthe channel cover member 28 is firmly affixed to the base member 26. Inthis embodiment, when containment compartment 12 is so formed, a channel34 is formed, which may advantageously house a wound suture 18.

In one embodiment, outer cover 22 may be provided with a plurality oftabs 46, for positioning within tab receiving members 44, to affix outercover 22 to base member 26 within outer periphery 30, to at leastpartially enclose medical device 14.

Further details regarding the construction and geometry of thecontainment compartments and packages formed therefrom are more fullydescribed in U.S. Pat. Nos. 6,047,815; 6,135,272 and 6,915,623, thecontents of each are hereby incorporated by reference in their entiretyfor all that they disclose.

Containment compartment 12 may be manufactured from conventionalmoldable materials. It is especially preferred to use polyolefinmaterials such as polyethylene and polypropylene, other thermoplasticmaterials, and polyester materials such as nylon, and equivalentsthereof. In one embodiment, the containment compartment 12 of thepresent invention may be injection molded, however, they may also beformed by other conventional processes and equivalents thereof,including thermo-forming. If desired, the packages may be manufacturedas individual assemblies or components which are then assembled.

The medical devices described herein are generally implantable medicaldevices and implants, including but not limited to mono andmultifilament sutures, surgical meshes such as hernia repair mesh,hernia plugs, brachy seed spacers, suture clips, suture anchors,adhesion prevention meshes and films, and suture knot clips. Alsoincluded are implantable medical devices that are absorbable andnon-absorbable.

An absorbable polymer is defined herein as a polymer that will degradeand be absorbed by the body over a period of time when exposed tophysiological conditions. Absorbable medical devices typically areformed from generally known, conventional absorbable polymers includingbut not limited to glycolide, lactide, copolymers of glycolide, ormixtures of polymers, such as polydioxanone, polycaprolactone, oxidizedregenerated cellulose and equivalents thereof. Preferably, the polymersinclude polymeric materials selected from the group consisting ofgreater than about 70% polymerized glycolide, greater than about 70%polymerized lactide, polymerized 1,4-dioxan-2-one, greater than about70% polypeptide, copolymers of glycolide and lactide, greater than about70% cellulosics and cellulosic derivatives. Preferably, absorbablemedical devices are made from polydioxanone, poliglecaprone, or aglycolide/lactide copolymer. Examples of absorbable medical deviceinclude mono and multifilament sutures. The multifilament sutureincludes sutures wherein a plurality of filaments is formed into abraided structure. Examples of non-absorbable medical devices includemono and multifilament sutures, surgical meshes such as hernia repairmesh, hernia plugs and brachy seed spacers, which may be polymeric ornonpolymeric. Non-absorbable medical devices may be made in whole or inpart from polymeric materials that include, but are not limited to,polyolefins such as polypropylene; polyamides such as nylon; chlorinatedand/or fluorinated hydrocarbons such as Teflon® material; or polyesterssuch as Dacron® synthetic polyesters; or from nonpolymeric materialsthat include, but are not limited to, silks, collagen, stainless steel,titanium, cobalt chromium alloy, nitinol. Preferably, the non-absorbablemedical devices are made from nylon or polypropylene.

In one embodiment, the sutures and needles that can be packaged in thepackages disclosed herein include conventional surgical needles andconventional bioabsorbable and nonabsorbable surgical sutures andequivalents thereof. The packages of the present invention are useful topackage small diameter sutures which were previously difficult topackage in tray packages because of removal or hang-up problems uponwithdrawal of such suture from the packages.

Suitable antimicrobial agents may be selected from, but are not limitedto, halogenated hydroxyl ethers, acyloxydiphenyl ethers, or combinationsthereof. In particular, the antimicrobial agent may be a halogenated2-hydroxy diphenyl ether and/or a halogenated 2-acyloxy diphenyl ether,as described in U.S. Pat. No. 3,629,477, and represented by thefollowing formula:

In the above formula, each Hal represents identical or different halogenatoms, Z represents hydrogen or an acyl group, and w represents apositive whole number ranging from 1 to 5, and each of the benzenerings, but preferably ring A can also contain one or several lower alkylgroups which may be halogenated, a lower alkoxy group, the allyl group,the cyano group, the amino group, or lower alkanoyl group. Preferably,methyl or methoxy groups are among the useful lower alkyl and loweralkoxy groups, respectively, as substituents in the benzene rings. Ahalogenated lower alkyl group, trifluoromethyl group is preferred.

Antimicrobial activity similar to that of the halogen-o-hydroxydiphenylethers of the above formula is also attained using the O-acylderivatives thereof which partially or completely hydrolyze under theconditions for use in practice. The esters of acetic acid, chloroaceticacid, methyl or dimethyl carbamic acid, benzoic acid, chlorobenzoicacid, methylsulfonic acid and chloromethylsulfonic acid are particularlysuitable.

One particularly preferred antimicrobial agent within the scope of theabove formula is 2,4,4′-trichloro-2′-hydroxydiphenyl ether, commonlyreferred to as triclosan (manufactured by Ciba Geigy under the tradename Irgasan DP300 or Irgacare MP). Triclosan is a white powdered solidwith a slight aromatic/phenolic odor. As may be appreciated, it is achlorinated aromatic compound which has functional groups representativeof both ethers and phenols.

Triclosan is a broad-spectrum antimicrobial agent that has been used ina variety of products, and is effective against a number of organismscommonly associated with SSIs. Such microorganisms include, but are notlimited to, genus Staphylococcus, Staphylococcus epidermidis,Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis,methicillin-resistant Staphylococcus aureus, and combinations thereof.

In addition to the antimicrobial agents described above, the medicaldevice optionally may have a biocide, a disinfectant and/or anantiseptic, including but not limited to alcohols such as ethanol andisopropanol; aldehydes such as glutaraldehyde and formaldehyde; anilidessuch as triclorocarbanilide; biguanides such as chlorhexidine;chlorine-releasing agents such as sodium hypochlorite, chlorine dioxideand acidified sodium chlorite; iodine-releasing agents such aspovidone-iodine and poloxamer-iodine; metals such as silver nitrate,silver sulfadiazine, other silver agents, copper-8-quinolate and bismuththiols; peroxygen compounds such as hydrogen peroxide and peraceticacid; phenols; quaternary ammonium compounds such as benzalkoniumchloride, cetrimide and ionenes-polyquaternary ammonium compounds. Themedical device optionally may have antibiotics, including but notlimited to penicillins such as amoxicillin, oxacillin and piperacillin;cephalosporins parenteral such as cefazolin, cefadroxil, cefoxitin,cefprozil, cefotaxime and cefdinir; monobactams such as aztreonam;beta-lactamase inhibitors such as clavulanic acid sulbactam;glycopeptide such as vancomycin; polymixin; quinolones such as nalidixicacid, ciprofloxacin and levaquin; metranidazole; novobiocin;actinomycin; rifampin; aminoglycosides such as neomycin and gentamicin;tetracyclines such as doxycycline; chloramphenicol; macrolide such aserythromycin; clindamycin; sulfonamide such as sulfadiazine;trimethoprim; topical antibiotics; bacitracin; gramicidin; mupirocin;and/or fusidic acid. Optionally, the medical device may haveantimicrobial peptides such as defensins, magainin and nisin; lyticbacteriophage; surfactants; adhesion blockers such as antibodies,oligosaccharides and glycolipids; oligonucleotides such as antisenseRNA; efflux pump inhibitors; photosensitive dyes such as porphyrins;immune modulators such as growth factors, interleukins, interferons andsynthetic antigens; and/or chelators such as EDTA, sodiumhexametaphosphate, lactoferrin and transferrin.

As shown in FIG. 3 , the antimicrobial agent may be delivered to themedical device from a plurality of antimicrobial agent reservoirs 56,attached to the inner surface of outer cover 22. Specifically, theantimicrobial agent is transferred from the antimicrobial agentreservoirs to the medical device when the package, the antimicrobialagent reservoirs and the medical device are subjected to time,temperature and pressure conditions, as described below. For example,the antimicrobial agent reservoirs may be antimicrobial agent-loadedpaper reservoirs, antimicrobial agent-loaded porous pouch reservoirs,antimicrobial agent-loaded plastic reservoirs, antimicrobialagent-loaded sponge or foam reservoirs, an antimicrobial agent-loadedtape or patch. As indicated above, in one form, the plurality ofantimicrobial agent reservoirs 56 may be a series of TYVEK® patches 54.

As indicated, the packaged antimicrobial medical devices disclosedherein utilize an adsorbent or absorbent material to improve shelf lifeover packaged antimicrobial sutures that do not utilize an adsorbent orabsorbent material. It has been shown that the shelf life of anantimicrobial medical device, such as a triclosan-containing suture, isbelieved to be limited by triclosan levels that increase over timeduring normal and accelerated storage conditions. It has beensurprisingly discovered that certain adsorbent or absorbent materialsmay serve as a buffering agent to moderate the rate of increase oftriclosan on the medical device.

In one embodiment, an adsorbent or absorbent material is provided bycoating the adsorbent or absorbent material on at least a portion of onesurface of the inner package, 11. In another embodiment, the adsorbentor absorbent material is provided by placing an adsorbent or absorbentsubstrate (not shown) within the outer package. In another embodiment,the adsorbent or absorbent substrate is formed by coating a substratewith an adsorbent or absorbent material. In yet another embodiment, theadsorbent or absorbent substrate is formed of an adsorbent or absorbentmaterial. In still yet another embodiment, the adsorbent or absorbentmaterial provided on at least a portion of one surface of the innerpackage, is provided on at least one surface of outer cover 22.

Materials having adsorbent or absorbent properties, include bentonite,activated carbon, activated alumina, silica gel, zeolite,super-absorbant polymers, humectants, polymeric coatings, groundpolymeric coatings, natural products, non-paper substrates, and clays,including kaolin. Clays, such as kaolin, have proven to be particularlyeffective.

Additionally, the medical device may optionally have a coating thereon,and/or may optionally comprise one or more surfaces having anantimicrobial agent disposed thereon prior to any transfer ofantimicrobial agent to the medical device from the antimicrobial agentsource. For example, it is advantageous to apply a coating compositionhaving an antimicrobial agent therein to the surface of the medicaldevice. Examples of medical devices, as well as coatings that may beapplied thereto, may be found in U.S. Pat. Nos. 4,201,216, 4,027,676,4,105,034, 4,126,221, 4,185,637, 3,839,297, 6,260,699, 5,230,424,5,555,976, 5,868,244, and 5,972,008, each of which is herebyincorporated herein in its entirety. As disclosed in U.S. Pat. No.4,201,216, the coating composition may include a film-forming polymerand a substantially water-insoluble salt of a C₆ or higher fatty acid.As another example, an absorbable coating composition that may be usedfor an absorbable medical device may include poly(alkylene oxylates)wherein the alkylene moieties are derived from C₆ or mixtures of C₄ toC₁₂ diols, which is applied to a medical device from a solvent solution,as disclosed in U.S. Pat. No. 4,105,034. The coating compositions mayinclude a polymer or copolymer, which may include lactide and glycolide,as a binding agent. The coating compositions may also include calciumstearate, as a lubricant; and an antimicrobial agent. The coating may beapplied to the device by solvent-based coating techniques, such as dipcoating, spray coating, or suspended drop coating, or any other coatingmeans.

Absorbable medical devices are moisture sensitive, that is, they aredevices that will degrade if exposed to moisture in the atmosphere or inthe body. It is known by those of ordinary skill in the art that medicaldevices made from absorbable polymers may deteriorate and lose theirstrength if they come into contact with water vapor prior to use duringsurgery. For instance, the desirable property of in vivo tensilestrength retention for sutures will be rapidly lost if the sutures areexposed to moisture for any significant period of time prior to use.Therefore, it is desirable to use a hermetically sealed package forabsorbable medical devices. A hermetically sealed package is definedherein to mean a package made of a material that serves as both asterile barrier and a gas barrier, i.e., prevents or substantiallyinhibits moisture and gas permeation.

Referring again to FIG. 5 , materials useful for constructing outerpackages 50 may include, for example, include single and multilayeredconventional metal foil products, often referred to as heat-sealablefoils. These types of foil products are disclosed in U.S. Pat. No.3,815,315, which is hereby incorporated by reference in its entirety.Another type of foil product that may be utilized is a foil laminatereferred to in the field of art as a peelable foil. Examples of suchpeelable foil and substrates are disclosed in U.S. Pat. No. 5,623,810,which is hereby incorporated by reference in its entirety. If desired,conventional non-metallic polymer films in addition to or in lieu ofmetal foil may be used to form the package for absorbable medicaldevices. Such films are polymeric and may include conventionalpolyolefins, polyesters, acrylics, halogenated hydrocarbons and thelike, combinations thereof and laminates. These polymeric filmssubstantially inhibit moisture and oxygen permeation and may be coatedwith conventional coatings, such as, for example, mineral and mineraloxide coatings that decrease or reduce gas intrusion. The package maycomprise a combination of polymer and metal foils, particularly amulti-layer polymer/metal-foil composite, such as a polyester/aluminumfoil/ethylacrylic acid laminate.

Nonabsorbable medical devices may be packaged in any of the materialsdescribed above. In addition, it is desirable to package nonabsorbablemedical devices in a package made of a material that serves as a sterilebarrier, such as a porous material, i.e., medical grade paper, or apolymeric film or fabric that is permeable to moisture and gas, i.e.,TYVEK® nonwoven material, manufactured by E. I. du Pont de Nemours andCompany of Wilmington, Del., and made from high-density polyethylenefibers. Preferably, nonabsorbable medical devices are packaged in thesame packaging materials that are used for absorbable medical devices,such as hermetically sealed packages, when it is desirable to haveantimicrobial medical devices having a shelf life of at least 6 months,preferably at least 1 year and most preferably at least 2 years.

Microorganisms of the genus Staphylococcus are the most prevalent of allof the organisms associated with device-related surgical site infection.S. aureus and S. epidermidis are commonly present on patients' skin andas such are introduced easily into wounds. An efficacious antimicrobialagent against Staphylococcus is 2,4,4′-trichloro-2′-hydroxydiphenylether. This compound has a minimum inhibitory concentration (MIC)against S. aureus of 0.01 ppm, as measured in a suitable growth mediumand as described by Bhargava, H. et al in the American Journal ofInfection Control, June 1996, pages 209-218. The MIC for a particularantimicrobial agent and a particular microorganism is defined as theminimum concentration of that antimicrobial agent that must be presentin an otherwise suitable growth medium for that microorganism, in orderto render the growth medium unsuitable for that microorganism, i.e., theminimum concentration to inhibit growth of that microorganism. Thephrases “an amount sufficient to substantially inhibit bacterialcolonization” and “an effective amount” of the antimicrobial agent, asused herein, are defined as the minimum inhibitory concentration for S.aureus or greater.

A demonstration of this MIC is seen in the disk diffusion method ofsusceptibility. A filter paper disk, or other object, impregnated with aparticular antimicrobial agent is applied to an agar medium that isinoculated with the test organism. Where the antimicrobial agentdiffuses through the medium, and as long as the concentration of theantimicrobial agent is above the minimum inhibitory concentration (MIC),none of the susceptible organism will grow on or around the disk forsome distance. This distance is called a zone of inhibition. Assumingthe antimicrobial agent has a diffusion rate in the medium, the presenceof a zone of inhibition around a disk impregnated with an antimicrobialagent indicates that the organism is inhibited by the presence of theantimicrobial agent in the otherwise satisfactory growth medium. Thediameter of the zone of inhibition is inversely proportional to the MIC.

Method for Making an Antimicrobial Medical Device

In accordance with the various methods of the present invention, amethod of making a packaged antimicrobial suture is provided. The methodincludes the steps of providing an inner package having a source ofantimicrobial agent, the source of antimicrobial agent comprising aplurality of patches, each patch having a pair of antimicrobial materialreservoirs; positioning at least one suture within the inner package,the at least one suture comprising one or more surfaces; covering theinner package with an outer package having an inner surface; andsubjecting the at least one suture, the inner package and the innersurface of the outer package to time, temperature and pressureconditions sufficient to transfer an effective amount of theantimicrobial agent from the antimicrobial agent source to the at leastone suture and the inner package, thereby substantially inhibitingbacterial colonization on the at least one suture and the inner package.

As will be described in more detail hereinbelow, the step of subjectingthe suture, the inner package and the inner surface of the outer packageto conditions sufficient to transfer an effective amount of theantimicrobial agent includes the steps of placing the outer packagehaving the inner package and the suture therein in a sterilization unit,heating the sterilization unit to a first temperature, adjusting thepressure in the sterilization unit to a first pressure value, injectingsteam into the sterilization unit to expose the inner surface of theouter package, the inner package and the suture to water vapor for afirst period of time, adjusting the pressure within the sterilizationunit to a second pressure value, introducing a chemical sterilizationagent into the sterilization unit, maintaining the chemicalsterilization agent in the sterilization unit for a second period oftime to render a sufficient amount of microorganisms non-viable,removing residual moisture and chemical sterilization agent from thesuture and drying the packaged antimicrobial suture to a desiredmoisture level. In one embodiment, the step of introducing a chemicalsterilization agent comprises introducing ethylene oxide gas into thesterilization unit.

In one embodiment, the medical device is directly exposed to theantimicrobial agent, i.e., the antimicrobial agent source is located inthe package having the medical device. For example, the package maycontain an antimicrobial agent source, may have an antimicrobial agentsource attached to the inner surface of the package, or theantimicrobial agent source may be integral with one or more packagingcomponent in the package or with the package itself. In theseembodiments, the medical device is positioned within the package and mayinitially be free of an antimicrobial agent or may initially compriseone or more surfaces having an antimicrobial agent disposed thereon. Asindicated, the package, the antimicrobial agent source and the medicaldevice are then subjected to time, temperature and pressure conditionssufficient to transfer an effective amount of the antimicrobial agentfrom the antimicrobial agent source to the medical device, therebysubstantially inhibiting bacterial colonization on the medical device.

In the case where the medical device is initially free of anantimicrobial agent, the antimicrobial agent is delivered to the medicaldevice from an antimicrobial agent source when the package, theantimicrobial agent source and the medical device are subjected to time,temperature and pressure conditions sufficient to transfer a portion ofthe antimicrobial agent from the antimicrobial agent source to themedical device.

In the case where the medical device initially comprises one or moresurfaces having an antimicrobial agent disposed thereon, the time,temperature and pressure conditions are sufficient to transfer a portionof each of the antimicrobial agent disposed on the medical device andthe antimicrobial agent in the antimicrobial agent source to the innersurface of the package, such that an effective amount of theantimicrobial agent is retained on the medical device, therebysubstantially inhibiting bacterial colonization on the medical deviceand the inner surface of the package. In this embodiment, the amount orconcentration of antimicrobial agent on the medical device is stabilizedby providing additional antimicrobial agent in the packagingenvironment.

Alternatively, the medical device may be positioned within a package,and the package having the medical device is exposed indirectly to anexternal antimicrobial agent source, i.e., the antimicrobial agentsource is external to the package having the medical device.Specifically, the antimicrobial agent source and the package having themedical device are subjected to time, temperature and pressureconditions sufficient to transfer an effective amount of theantimicrobial agent from the antimicrobial agent source to the medicaldevice within the package, thereby substantially inhibiting bacterialcolonization on the medical device. In this embodiment, the package maybe made from a material that serves as a sterile barrier, such as aporous material or polymeric film that is permeable to moisture and gas,such that a gaseous antimicrobial agent source is capable of permeatingor transmitting as a vapor through the package. For example, the packagehaving the medical device may be placed in a sealed environment, and theantimicrobial agent source may be contained within the sealedenvironment or may be subsequently introduced to the sealed environment.The antimicrobial agent source may be any vapor form of theantimicrobial agent.

The rate of transfer of an antimicrobial agent such as triclosan fromthe antimicrobial agent source to the medical device is substantiallydependent upon the time, temperature and pressure conditions under whichthe package and the medical device are processed, stored and handled.The conditions to effectively transfer an antimicrobial agent such astriclosan include a closed environment, atmospheric pressure, atemperature of greater than 40° C., for a period of time ranging from 4to 8 hours. Also included are any combinations of pressure andtemperature to render a partial pressure for the antimicrobial agentthat is the same as or greater than the partial pressure rendered underthe conditions described above, in combination with a period of timesufficient to render an effective amount or concentration of theantimicrobial agent on the medical device, i.e., the minimum inhibitoryconcentration (MIC) for S. aureus or greater. Specifically, it is knownto one of ordinary skill that if the pressure is reduced, thetemperature may be reduced to effect the same partial pressure.Alternatively, if the pressure is reduced, and the temperature is heldconstant, the time required to render an effective amount orconcentration of the antimicrobial agent on the medical device may beshortened. Generally, the amount of antimicrobial agent in theantimicrobial agent source is at least that amount which is necessary todeliver the effective amount of the antimicrobial agent on the medicaldevice, when exposed to the conditions described below.

Medical devices typically are sterilized to render microorganismslocated thereon substantially non-viable. In particular, sterile isunderstood in the field of art to mean a minimum sterility assurancelevel of 10⁻⁶. Examples of sterilization processes are described in U.S.Pat. Nos. 3,815,315, 3,068,864, 3,767,362, 5,464,580, 5,128,101 and5,868,244, each of which is incorporated herein in its entirety.Specifically, absorbable medical devices may be sensitive to radiationand heat. Accordingly, it may be desirable to sterilize such devicesusing conventional sterilant gases or agents, such as, for example,ethylene oxide gas.

An ethylene oxide sterilization process is described below, since thetime, temperature and pressure conditions sufficient to transfer theantimicrobial agent from the antimicrobial agent source to the medicaldevice, are present in an ethylene oxide sterilization process. Howeverthe time, temperature and pressure conditions sufficient to transfer theantimicrobial agent from the antimicrobial agent source to the medicaldevice, may be effected alone or in other types of sterilizationprocesses, and are not limited to an ethylene oxide sterilizationprocess or to sterilization processes in general.

As discussed above, absorbable medical devices are sensitive to moistureand are therefore often packaged in hermetically sealed packages, suchas sealed foil packages. However, sealed foil packages are alsoimpervious to sterilant gas. In order to compensate for this and utilizefoil packages in ethylene oxide gas sterilization processes, processeshave been developed using foil packages having gas permeable or perviousvents (e.g., TYVEK® nonwoven material, manufactured by E. I. du Pont deNemours and Company of Wilmington, Del.). The gas permeable vents aremounted to an open end of the package and allow the passage of air,water vapor and ethylene oxide into the interior of the package. Afterthe sterilization process is complete, the package is sealed adjacent tothe vent so the vent is effectively excluded from the sealed package,and the vent is cut away or otherwise removed, thereby producing a gasimpervious hermetically sealed package. Another type of foil packagehaving a vent is a pouch-type package having a vent mounted adjacent toan end of the package, wherein the vent is sealed to one side of thepackage creating a vented section. After the sterilization process iscomplete the package is sealed adjacent to the vented section, and thesealed package is cut away for the vented section.

In one embodiment, the antimicrobial agent source is placed within thepackage, attached to the inner surface of the package, or is integralwith one or more packaging component in the package or with the packageitself. After the peripheral seal and side seals have been formed in thepackage, the packaged medical device may be placed into a conventionalethylene oxide sterilization unit. If the package is a foil package, theantimicrobial agent source may be any of the antimicrobial agent sourcesdescribed above or the antimicrobial agent source may be anantimicrobial agent loaded-gas permeable vent. For example, anantimicrobial agent such as triclosan may be loaded onto a TYVEK® gaspermeable vent by coating the TYVEK® strip with a solution of ethylacetate and triclosan; the antimicrobial agent loaded gas permeable ventis positioned within a package by mounting it to a hermetic packagingmaterial; the medical device is positioned within the hermetic packagingmaterial; the periphery of the hermetic packaging material is sealed ina manner to enclose the medical device and to allow the passage of gasinto the interior of the hermetic packaging material through the vent;the packaging material having the antimicrobial agent loaded gaspermeable vent and the medical device is subjected to time, temperatureand pressure conditions sufficient to transfer an effective amount ofthe antimicrobial agent from the antimicrobial agent loaded gaspermeable vent to the medical device; the packaging material is sealedto enclose the medical device and exclude the vent; and the vent is cutaway to thereby produce an antimicrobial medical device.

In another embodiment, the antimicrobial agent source may be introducedinto the sterilization or other unit external to the package having themedical device. For example, the medical device is positioned within thepackage; the package having the medical device is exposed to anantimicrobial agent source; and the package having the medical deviceand the antimicrobial agent source is subjected to time, temperature andpressure conditions sufficient to transfer an effective amount of theantimicrobial agent from the antimicrobial agent source to the medicaldevice within the package, thereby substantially inhibiting bacterialcolonization on the medical device. The package may be made from amaterial that serves as a sterile barrier, such as a porous material ora polymeric film that is permeable to moisture and gas, or from amaterial that results in a hermetically sealed package.

Prior to the start of the cycle, the sterilization unit may be heated toan internal temperature of about 25° C. The sterilization unit ismaintained about 22 to 37° C. throughout the humidification andsterilization cycles. Next, a vacuum may be drawn on the sterilizationunit to achieve a vacuum of approximately 1.8 to 6.0 kPa. In ahumidification cycle, steam then may be injected to provide a source ofwater vapor for the product to be sterilized. The packaged medicaldevices may be exposed to water vapor in the sterilization unit for aperiod of time of about 60 to 90 minutes. Times may vary, however,depending upon the medical device being sterilized.

Following this humidification portion of the cycle, the sterilizationunit may be pressurized by the introduction of dry inert gas, such asnitrogen gas, to a pressure of between about 42 and 48 kPa. Once thedesired pressure is reached, pure ethylene oxide may be introduced intothe sterilization unit until the pressure reaches about 95 kPa. Theethylene oxide may be maintained for a period of time effective tosterilize the packaged medical device. For example, the ethylene oxidemay be maintained in the sterilization unit for about 360 to about 600minutes for surgical sutures. The time required to sterilize othermedical devices may vary depending upon the type of product and thepackaging. The ethylene oxide then may be evacuated from thesterilization unit and the unit may be maintained under vacuum at apressure of approximately 0.07 kPa for approximately 150 to 300 minutesin order to remove residual moisture and ethylene oxide from thesterilized packaged medical devices. The pressure in the sterilizationunit may be returned to atmospheric pressure.

The following stage of the process is a drying cycle. The packagedmedical device may be dried by exposure to dry nitrogen and vacuum overa number of cycles sufficient to effectively remove residual moistureand water vapor from the packaged medical device to a preselected level.During these cycles, the packaged medical device may be subjected to anumber of pressure increases and decreases, at temperatures greater thanroom temperature. Specifically, the jacket temperature of the dryingchamber may be maintained at a temperature of between approximately 53°C. to 57° C. throughout the drying cycle. Higher temperatures, however,may be employed, such as about 65° C. to 70° C. for sutures, and higherdepending upon the medical device being sterilized. A typical dryingcycle includes the steps of increasing the pressure with nitrogen toapproximately 100 kPa, evacuating the chamber to a pressure ofapproximately 0.07 kPa over a period of 180 to 240 minutes,reintroducing nitrogen to a pressure of 100 kPa and circulating thenitrogen for approximately 90 minutes, evacuating the chamber to apressure of approximately 0.01 kPa over a period of approximately 240 to360 minutes and maintaining a pressure of not more than 0.005 kPa for anadditional 4 to 96 hours. At the end of the humidification,sterilization and drying cycles, which takes typically about 24 hours,the vessel is returned to ambient pressure with dry nitrogen gas. Oncedrying to the preselected moisture level is complete, the packagedmedical device may be removed from the drying chamber and stored in ahumidity controlled storage area.

Upon completion of the sterilization process, the antimicrobial medicaldevice, the package and/or the packaging component have thereon anamount of the antimicrobial agent effective to substantially inhibitcolonization of bacteria on or adjacent the antimicrobial device, thepackage and/or the packaging component.

As indicated above, it has been shown that the shelf life of anantimicrobial medical device, such as a triclosan-containing suture, canbe limited by increasing levels of triclosan that occur during normaland accelerated storage conditions. In some case, shelf life is limitedto a period not to exceed two years, due to the impact of thisphenomenon. The packaged antimicrobial medical devices disclosed hereinutilize an adsorbent or absorbent material to improve shelf life overpackaged antimicrobial sutures that do not utilize an adsorbent orabsorbent material. In accordance with the methods disclosed herein, inone embodiment, the method of making a packaged antimicrobial deviceincludes the step of coating the adsorbent or absorbent material on atleast a portion of one surface of the inner package. In anotherembodiment, the adsorbent or absorbent material is provided by placingan adsorbent or absorbent substrate within the outer package. In stillanother embodiment, the adsorbent or absorbent substrate is formed bycoating a substrate with an adsorbent or absorbent material. In a stillfurther embodiment, the adsorbent or absorbent substrate is formed of anadsorbent or absorbent material. In a yet still further embodiment, theinner package comprises a universal envelope formed from a paperboardstock having at least one surface coated with an adsorbent or absorbentmaterial.

Adsorbent or absorbent materials include bentonite, activated carbon,activated alumina, silica gel, zeolite, super-absorbant polymers,humectants, polymeric coatings, ground polymeric coatings, naturalproducts, non-paper substrates, and clays, including kaolin. Clays, suchas kaolin, have proven to be particularly effective.

In one embodiment, a method of increasing the shelf life of a packagedantimicrobial medical device is provided. The method includes the stepsof providing an inner package having a source of antimicrobial agent,providing an adsorbent or absorbent material effective to adsorb aportion of the antimicrobial agent over time, positioning a medicaldevice within the inner package, the medical device comprising one ormore surfaces, covering the inner package with an outer package havingan inner surface and subjecting the medical device, the inner packageand the inner surface of the outer package to time, temperature andpressure conditions sufficient to transfer an effective amount of theantimicrobial agent from the antimicrobial agent source to the medicaldevice and the inner package, thereby substantially inhibiting bacterialcolonization on the medical device and the inner package. The packagedantimicrobial medical device exhibits improved shelf life over apackaged antimicrobial medical device without an adsorbent or absorbentmaterial so provided.

All patents, test procedures, and other documents cited herein,including priority documents, are fully incorporated by reference to theextent such disclosure is not inconsistent and for all jurisdictions inwhich such incorporation is permitted.

While the illustrative embodiments disclosed herein have been describedwith particularity, it will be understood that various othermodifications will be apparent to and can be readily made by thoseskilled in the art without departing from the spirit and scope of thedisclosure. Accordingly, it is not intended that the scope of the claimsappended hereto be limited to the examples and descriptions set forthherein but rather that the claims be construed as encompassing all thefeatures of patentable novelty which reside herein, including allfeatures which would be treated as equivalents thereof by those skilledin the art to which this disclosure pertains.

When numerical lower limits and numerical upper limits are listedherein, ranges from any lower limit to any upper limit are contemplated.

What is claimed:
 1. A method of making a packaged antimicrobial medicaldevice, comprising: providing a package having at least an inner surfaceand an outer surface; positioning at least one medical device within thepackage; providing a source of antimicrobial agent external to thepackage; subjecting the medical device, at least the inner surface ofthe package and the antimicrobial agent source to time, temperature, andpressure conditions sufficient to transfer an effective amount of theantimicrobial agent from the antimicrobial agent source to the medicaldevice and the inner surface of the package, thereby substantiallyinhibiting bacterial colonization on the medical device and the innerpackage surface; and providing an adsorbent or absorbent material withinthe package, wherein an inner package comprises a containmentcompartment that includes a plurality of patches, each patch having atleast a pair of reservoirs formed of a porous medical grade paper or apermeable polymeric film or a fabric having a matrix structure, and anouter cover, the outer cover having one surface coated with theadsorbent or absorbent material.
 2. The method of making a packagedantimicrobial medical device according to claim 1, wherein the adsorbentor absorbent material is formed by coating a substrate with an adsorbentmaterial.
 3. The method of making a packaged antimicrobial medicaldevice according to claim 1, wherein the medical device positionedwithin the inner package is substantially free of antimicrobial agent.4. The method of making a packaged antimicrobial medical deviceaccording to claim 1, wherein the antimicrobial agent is selected fromthe group consisting of halogenated hydroxyl ethers, acyloxydiphenylethers, and combinations thereof.
 5. The method of making a packagedantimicrobial medical device according to claim 1, wherein the effectiveamount of the antimicrobial agent transferred from the source ofantimicrobial agent to the medical device and the inner package istransferred during an ethylene oxide sterilization process.
 6. Themethod of making a packaged antimicrobial medical device according toclaim 1, wherein the step of subjecting the medical device and the innersurface of the package to conditions sufficient to transfer an effectiveamount of the antimicrobial agent comprises the steps of: placing thepackage and the medical device therein in a sterilization unit; heatingthe sterilization unit to a first temperature; adjusting the pressure inthe sterilization unit to a first pressure value; injecting steam intothe sterilization unit to expose the package and the medical device towater vapor for a first period of time; adjusting the pressure withinthe sterilization unit to a second pressure value; introducing achemical sterilization agent into the sterilization unit; maintainingthe chemical sterilization agent in the sterilization unit for a secondperiod of time to render a sufficient amount of microorganismsnon-viable; removing residual moisture and chemical sterilization agentfrom the medical device; and drying the packaged antimicrobial medicaldevice to a desired moisture level.
 7. The method of making a packagedantimicrobial medical device according to claim 6, wherein the step ofintroducing a chemical sterilization agent comprises introducingethylene oxide gas into the sterilization unit.
 8. The method of makinga packaged antimicrobial medical device according to claim 1, whereinthe medical device is selected from a suture, a surgical mesh, a herniaplug, a brachy seed spacer, a suture clip, a suture anchor, an adhesionprevention mesh or film or a suture knot clip.
 9. The method of making apackaged antimicrobial medical device according to claim 1, wherein thepackage including the medical device is placed in a sealed environmentand the antimicrobial agent source is contained in the sealedenvironment.
 10. The method of making a packaged antimicrobial medicaldevice according to claim 1, wherein the package including the medicaldevice is placed in a sealed environment and the antimicrobial agentsource is subsequently introduced into the sealed environment.
 11. Amethod of making a packaged antimicrobial suture, the method comprisingthe steps of: providing an inner package having a source ofantimicrobial agent, the source of antimicrobial agent comprising aplurality of patches, each patch having at least a pair of antimicrobialagent reservoirs; positioning at least one suture within the innerpackage, the at least one suture comprising one or more surfaces;covering the inner package with an outer package having an innersurface; and subjecting the at least one suture, the inner package, andthe inner surface of the outer package to time, temperature, andpressure conditions sufficient to transfer an effective amount of theantimicrobial agent from the antimicrobial agent source to the at leastone suture and the inner package, thereby substantially inhibitingbacterial colonization on the at least one suture and the inner package,wherein said antimicrobial agent reservoirs are formed of a porousmedical grade paper or a permeable polymeric film.
 12. A method ofmaking a packaged antimicrobial suture, the method comprising the stepsof: providing an antimicrobial agent from an external source to an innerpackage the inner package comprising a containment compartment having abase member and a channel cover member, the base member including anouter periphery, and an outer cover positioned upon channel cover memberand within the outer periphery, to at least partially enclose at leastone suture within the inner package, the at least one suture comprisingone or more surfaces; covering the inner package with an outer packagehaving an inner surface; and subjecting the at least one suture, theinner package, and the inner surface of the outer package to time,temperature, and pressure conditions sufficient to transfer an effectiveamount of the antimicrobial agent from the antimicrobial agent source tothe at least one suture and the inner package, thereby substantiallyinhibiting bacterial colonization on the at least one suture and theinner package.
 13. The method of making a packaged antimicrobial sutureaccording to claim 12, wherein the antimicrobial agent is selected fromthe group consisting of halogenated hydroxyl ethers, acyloxydiphenylethers, and combinations thereof.
 14. The method of making a packagedantimicrobial suture according to claim 12, wherein the antimicrobialagent is selected from the group consisting of halogenated hydroxylethers, acyloxydiphenyl ethers, and combinations thereof.